JP4046360B2 - Process for the production of arylsulfonyl chlorides - Google Patents
Process for the production of arylsulfonyl chlorides Download PDFInfo
- Publication number
- JP4046360B2 JP4046360B2 JP53933698A JP53933698A JP4046360B2 JP 4046360 B2 JP4046360 B2 JP 4046360B2 JP 53933698 A JP53933698 A JP 53933698A JP 53933698 A JP53933698 A JP 53933698A JP 4046360 B2 JP4046360 B2 JP 4046360B2
- Authority
- JP
- Japan
- Prior art keywords
- chloride
- reaction
- chloropyridine
- methoxy
- methylpyrazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims description 45
- -1 arylsulfonyl chlorides Chemical class 0.000 title claims description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 27
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- MFJSIQDQIZEVJX-UHFFFAOYSA-N 2-chloropyridine-3-sulfonyl chloride Chemical compound ClC1=NC=CC=C1S(Cl)(=O)=O MFJSIQDQIZEVJX-UHFFFAOYSA-N 0.000 claims description 13
- 239000012954 diazonium Substances 0.000 claims description 13
- 150000001989 diazonium salts Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 7
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- JQJOGAGLBDBMLU-UHFFFAOYSA-N pyridine-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=N1 JQJOGAGLBDBMLU-UHFFFAOYSA-N 0.000 claims description 7
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000003927 aminopyridines Chemical class 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229940045803 cuprous chloride Drugs 0.000 claims description 6
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 6
- 230000027756 respiratory electron transport chain Effects 0.000 claims description 6
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 4
- CDVMCGIOTMQKOU-UHFFFAOYSA-N 2-methylpropyl n-(2-chloropyridin-3-yl)sulfonyl-n-(3-methoxy-5-methylpyrazin-2-yl)carbamate Chemical compound COC1=NC(C)=CN=C1N(C(=O)OCC(C)C)S(=O)(=O)C1=CC=CN=C1Cl CDVMCGIOTMQKOU-UHFFFAOYSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical group Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- JRIUSNXEAMPSCD-UHFFFAOYSA-N 2-methylpropyl n-(3-methoxy-5-methylpyrazin-2-yl)carbamate Chemical compound COC1=NC(C)=CN=C1NC(=O)OCC(C)C JRIUSNXEAMPSCD-UHFFFAOYSA-N 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 claims description 2
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 2
- NKFLEFWUYAUDJV-UHFFFAOYSA-N pyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN=C1 NKFLEFWUYAUDJV-UHFFFAOYSA-N 0.000 claims description 2
- 125000006243 carbonyl protecting group Chemical group 0.000 claims 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 102000002045 Endothelin Human genes 0.000 description 2
- 108050009340 Endothelin Proteins 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- MFZUXRKTKZKWSS-UHFFFAOYSA-N benzene;sulfuryl dichloride Chemical class ClS(Cl)(=O)=O.C1=CC=CC=C1 MFZUXRKTKZKWSS-UHFFFAOYSA-N 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 description 1
- KFBKRCXOTTUAFS-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 KFBKRCXOTTUAFS-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 150000003142 primary aromatic amines Chemical class 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IAUBZYYUBMBVPI-UHFFFAOYSA-N pyridine;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.C1=CC=NC=C1 IAUBZYYUBMBVPI-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
-
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Description
本発明は新規な化学プロセスに関し、そして、より詳細には、ピリジンスルホニルクロリドおよび特定のベンゼンスルホニルクロリドの製造のための新規な化学プロセスに関する。
ピリジンスルホニルクロリドおよびベンゼンスルホニルクロリドは、種々の用途を有する化合物の製造、例えば、医薬または除草剤の製造において有用である。例えば、2-クロロピリジン-3-スルホニルクロリドは、国際特許出願公開番号WO 96／40681に記載のエンドセリンアンタゴニストの製造において特に有用である。
ピリジンスルホニルクロリド(例えば2-クロロピリジン-3-スルホニルクロリド)およびベンゼンスルホニルクロリドの調製のための多くの方法が公知である。このような方法の1つは、対応のアミノピリジン(例えば3-アミノ-2-クロロピリジン)または芳香族アミンのジアゾニウム塩と二酸化硫黄とを酢酸存在下、CuClまたはCuCl2を触媒として使用して反応させ、次いで生成物を溶媒抽出によって単離することを伴う。このような方法はWO 96／40681および欧州特許出願公開番号第733629号および同第618209号に開示される。同様の方法はSynthesis, (1969), 第6巻, 第1号、第3-10頁およびRec. Trav. Chim., (1965), 84, 24-29頁に開示される。
このプロセスを大規模に行う場合の欠点は、反応の最後に不純物を含まない生成物を単離することに関する困難性である。特に、酢酸を含まない生成物を得ること、あるいは後処理時に生成物が加水分解して対応のスルホン酸となることを防ぐことが、大規模の場合にはしばしば困難である。このプロセスを大規模で行う場合のさらなる欠点は、気体状の試薬である二酸化硫黄を使用することである。これらの欠点のため、このプロセスは商業的規模での操作としては魅力に欠ける。
驚くべきことに、酢酸および二酸化硫黄ガスの両方の使用を回避し、かつ公知のプロセスが直面する単離の問題を克服する、ピリジンスルホニルクロリドおよび特定のベンゼンスルホニルクロリドの製造のためのプロセスが今や発見された。
本発明によれば、ピリジンスルホニルクロリドまたはベンゼンスルホニルクロリド(ここでベンゼン環は1つ以上の電子吸引性基を有する)の製造のためのプロセスが提供され、このプロセスは、アミノピリジンまたはアミノベンゼン(ここでベンゼン環は1つ以上の電子吸引性基を有する)のジアゾニウム塩と水中の塩化チオニルの混合物との、電子移動触媒存在下での反応を包含する。
本発明の特定の局面はピリジンスルホニルクロリドの製造のためのプロセスであり、このプロセスは、アミノピリジンのジアゾニウム塩と水中の塩化チオニルの混合物との、電子移動触媒存在下での反応を包含する。
本発明のさらなる特定の局面は、ベンゼンスルホニルクロリドの製造のためのプロセスであり、ここでベンゼン環は1つ以上の電子吸引性基(より詳細には1つまたは2つの電子吸引性基)を有し、このプロセスは、アミノベンゼンのジアゾニウム塩(ここでベンゼン環は1つ以上の電子吸引性基を有する)と水中の塩化チオニルの混合物との、電子移動触媒存在下での反応を包含する。
ピリジンスルホニルクロリドまたはアミノピリジンに言及する場合、ピリジン環は未置換でもよく、あるいは1つ以上の置換基を有していてもよいことが理解される。具体的な置換基としては、例えば、電子吸引性置換基が挙げられる。
好ましい電子移動触媒としては、例えば、塩化第二銅(CuCl2)および塩化第一銅(CuCl)が挙げられ、特に後者である。好ましくは0.012から0.05当量の触媒(アミノ化合物1当量当たり)が使用される。
官能基または置換基は、水素に対して相対的に電子吸引性(−I)基または電子供与性(＋I)基に分類され得ることが、J. MarchによってAdvanced Organic Chemistry, 第4版、Wiley & Sonsに開示されているように周知である。典型的な電子吸引性基は上記刊行物に参照され、あるいは列挙されており、これらは本明細書中に参考として援用される。具体的な電子吸引性基としては、例えば、クロロ、ブロモ、シアノ、ニトロ、およびカルボキシが挙げられる。
第一級芳香族アミンまたはヘテロ芳香族アミンのジアゾニウム塩の調製は有機化学の分野で周知であり、アミンと亜硝酸との反応による。本発明のプロセスのためには、アルカリ金属亜硝酸塩(特に亜硝酸ナトリウム)と鉱酸(特に塩酸)との、アミノ化合物存在下での反応という従来の方法によって、亜硝酸をインサイチュで発生させることが便利である。ジアゾ化反応は一般に約＋5〜−10℃、そして好ましくは＋1〜−4℃の範囲の温度で行われる。約1〜1.2当量のアルカリ金属亜硝酸塩および3〜20(より好ましくは11〜13)当量の濃(約36％)塩酸を(アミノ化合物1当量当たり)使用することが好ましい。出発物質が1つ以上の電子吸引性基を有するアミノベンゼンである場合、アミンを鉱酸に添加し、そしてこの混合物を(塩形成の完了を確実にするために)30〜50℃で10〜60分間加熱し、その後冷却し、そして亜硝酸ナトリウム水溶液を加えることが好ましい。亜硝酸ナトリウムを溶解するために加えられる水は通常、アミノ化合物の投入重量を基準にして1〜5容量の間であるが、その代わりに、塩酸中のアミンの混合物に固体亜硝酸塩を少しずつ加えてもよい。ジアゾニウム塩は不安定であるので、このようにして生成されたジアゾニウム塩溶液またはスラリーを、溶液またはスラリーの温度を添加の間中、約＋1〜−4℃の間に維持しながら、調製の直後に使用することが好ましい。
1当量のアミノ化合物当たり、2〜12当量の塩化チオニルを使用することが好ましく、そして特に4〜5当量の塩化チオニルを使用することが好ましい。
塩化チオニルの溶解のために添加される水は、アミノ化合物の投入重量を基準にして、5〜30容量(そしてより好ましくは10〜20容量)の間の水であることが好ましい。
塩化チオニルおよび水の混合物を、ジアゾニウム塩との反応の前に、18〜25℃(便利には周囲温度付近)で1〜48時間(便利には15〜20時間(例えば終夜))維持することが好ましい。
ジアゾニウム塩の溶液は、−10℃と＋5℃との間、および好ましくは−4℃と＋1℃との間の温度で一貫した発熱反応を維持して、可能な限り短時間で添加することが好ましい。添加の後、反応をこの温度付近で、15〜90分間維持することが好ましい。
生成物は、適切な溶媒、例えば、炭化水素、塩素化炭化水素、または水と混和しないエーテル溶媒(例えば、ジクロロメタン、ジエチルエーテルまたは好ましくはトルエン)の中への抽出により単離され得る。反応混合物中に酢酸が存在しないことは、溶媒抽出物中の酢酸の存在(およびその後のその除去)に関連する困難性が回避されることを意味する。抽出溶媒としてトルエンを使用する利点は、抽出物を水で洗浄し得、そして任意の残留する微量の水および同伴されるHClが共沸蒸留によって除去され得、生成物がトルエン溶液として得られることであり、このトルエン溶液は次にその後の反応に直接使用され得、あるいはトルエンを減圧下除去して生成物を得ることができ、この生成物は、例えば、n-ヘキサン、イソヘキサンまたはシクロヘキサンのような無極性溶媒から高純度で再結晶され得る。
あるいは、生成物が固体のスルホニルクロリドである場合、これは反応混合物から沈殿し得、そして溶媒抽出の代わりに濾過によって採取され得る。
本発明のプロセスは、2-ハロゲノピリジン-3-スルホニルクロリド、例えば2-クロロピリジン-3-スルホニルクロリドの調製に特に適する。
本発明のプロセスを2-クロロ-3-ピリジンスルホニルクロリドの調製に使用する場合に見いだされるさらなる驚くべき利点は、生成物が反応混合物から遊離塩基として高純度で沈殿し、そしてこれを濾過によって採取し得ることである。3-アミノ-2-クロロピリジンのジアゾニウム塩から2-クロロ-3-ピリジンスルホニルクロリドを調製するための今までの公知の方法は全て、反応に酢酸を使用するので、抽出による単離を必要とすると考えられる。
本発明はまた、WO 96／40681(これは本明細書中に参考として援用される)に開示される特定のエンドセリンアンタゴニストの調製のためのプロセスを提供する。
それゆえ、他の局面によれば、本発明は式Ｉの化合物
(a) 3-アミノ-2-クロロピリジンのジアゾニウム塩と水中の塩化チオニルの混合物との電荷移動触媒存在下での反応により、2-クロロピリジン-3-スルホニルクロリドを与える工程；
(b) 2クロロピリジン-3-スルホニルクロリドとイソブチルN-(3-メトキシ-5-メチルピラジン-2-イル)カルバメートとの水素化アルカリ金属存在下での不活性溶媒中での反応により、2クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドを与える工程；
(c) 2-クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドと式IIのボロン酸
その後、式Ｉの化合物の薬学的に受容可能な塩が必要とされる場合、これは生理学的に受容可能なイオンを与える適切な酸または塩基との反応によって得られ、あるいは任意の他の従来の塩形成手順によって得られる。
工程(a)は上記のように行われ得る。
工程(b)は、例えば、水素化アルカリ金属(例えば水素化ナトリウムまたは水素化カリウム)をDMF、ピリジンまたはトルエンのような不活性溶媒中で用いて行われ得る。この反応は、例えば０℃〜70℃の範囲の温度で行われる。工程(b)の典型的な例はWO 96/40681の実施例１(ii)に記載される。例えば、化合物イソブチルN-(3-メトキシ-5-メチルピラジン-2-イル)カルバメートがWO 96/40681の実施例1に記載のように得られ得る。
工程(c)において、適切な触媒としては、例えば、テトラキス(トリフェニルホスフィン)ニッケル(0)、ビス(トリフェニルホスフィン)ニッケル(II)クロリド、ニッケル(II)クロリド、ビス(トリフェニルホスフィン)パラジウム(II)クロリド、パラジウム(II)クロリド、およびテトラキス(トリフェニルホスフィン)パラジウム(0)が挙げられ、この中で最後のものが好ましい触媒である。反応で使用するための適切な塩基は、例えば、アルカリ金属アルコキシド(例えば、ナトリウムメトキシドまたはナトリウムエトキシド)、アルカリ金属水酸化物(例えば、水酸化ナトリウムまたは水酸化カリウム)、アルカリ金属炭酸塩(例えば、炭酸ナトリウムまたは炭酸カリウム)、または有機塩基(例えば、トリ(1-6C)アルキルアミン、例えば、トリエチルアミン)が挙げられる。これらの中で、炭酸ナトリウムが好ましい塩基である。カップリングは通常、適切な溶媒または希釈剤、例えば、炭化水素(例えばトルエンまたはキシレン)、エーテル(例えば、ジオキサンまたはテトラヒドロフラン)、(1-4C)アルコール(例えば、メタノール、エタノールまたはブタノール)、水またはそれらの混合物(例えば、トルエン、エタノールおよび水の混合物であり、これが好ましい)の存在下で行われる。反応は通常、例えば50〜150℃の範囲の温度で行われ、そして便利には、使用される溶媒または溶媒混合物の還流温度またはその付近で行われる。工程(c)の例はWO 96/40681の実施例1(iii)、11(ii)、12(ii)、13(ii)、14(ii)、58(vii)および64(iv)に記載される。あるいは、カップリングはフッ化物イオン源を用いて水性条件下で行われ得、例えば、WO 96/40681の実施例30(ii)と同じように、トルエンおよび水の混合物中、還流下、フッ化カリウムを用いて行われる。
イソブトキシカルボニル保護基の除去は、保護生成物の塩基性条件下での単離の後に行われ得、例えば、メタノールのような適切な溶媒中で水酸化ナトリウムまたはアルコキシド(例えばメトキシド)を用いて行われ得る(例えば、WO 96/40681の実施例1、11、12、13、14、58および64に記載のように)。あるいは、イソブトキシカルボニル基は、例えば、反応混合物にさらなる水を加えることによって、インサイチュの加水分解によって除去され得る。
このプロセスは式IにおいてRが2-カルボキシ-2-メチルプロピルである化合物の調製に特に適する。
他の局面によれば、本発明は、Rが1,3,4-オキサジアゾール-2-イルである式Iの化合物の調製のためのプロセスを提供する。このプロセスは上記の工程(a)および(b)を包含し、次に以下の追加工程：
(i) 2-クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドと4-メトキシカルボニルフェニルボロン酸(あるいはその無水物またはエステル)とのフッ化物イオン源存在下および水性条件下での反応により、N-(イソブトキシカルボニル)-2-(4-メトキシカルボニルフェニル)-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドを与える工程；
(ii)イソブトキシカルボニル保護基の除去工程；
(iii)メチルエステル(-CO.OCH3)基を対応のヒドラジド(-CONHNH2)に転化する工程；および
(iv)ヒドラジド基を1,3,4-オキサジアゾール-2-イル部分に転化する工程；を包含し、その後、式Ｉの化合物の薬学的に受容可能な塩が必要とされる場合、これは生理学的に受容可能なイオンを与える適切な酸または塩基との反応によって得られ、あるいは任意の他の従来の塩形成手順によって得られる。
工程(i)は、例えば、フッ化物イオン源としてフッ化カリウムを用い、そして溶媒として、キシレン、メタノールおよび水、またはトルエンと水との混合物を用いて行われ得る。反応は便利には使用される溶媒混合物の還流温度にて行われる。工程(i)の典型的な例は、WO 96/40681の実施例30(ii)に例証される。
工程(ii)は、例えば、塩基性条件下で行われ得、例えば、メタノールとアンモニア水との混合物、あるいはメタノール中のナトリウムメトキシドを用いて行われ得る。これは、(i)で得られた生成物を初めに単離した後に行われ得(WO 96/40681の実施例32に示すように)、あるいは(i)の反応混合物を水で希釈し、そして有機相を分離し、濾過し、そして濾液をメタノールで希釈し、次いでアンモニア水を加えてもよい。次に生成物は、水を加えることによって単離され得、そして酢酸を加えることによって沈殿し得る。
工程(iii)は、例えば、工程(ii)の生成物を適切な溶媒(例えばジクロロメタンおよび水)中でヒドラジン水和物と反応させることによって行われ得る。ヒドラジドはヒドラジン塩として沈殿し、そして水性塩酸を加えることによって遊離ヒドラジドに転化され得、そして濾過によって単離される。
工程(iv)は、例えば、過剰のトリエチルオルトギ酸塩中の工程(iii)の生成物の混合物を24時間還流することによって行われ得る。生成物は冷却すると沈殿する。あるいは、工程(ii)、(iii)および(iv)は、WO 96/40681の実施例36に示すように、工程(i)の生成物を、還流下、メタノール、エタノール、アセトニトリルまたはテトラヒドロフランのような溶媒中でヒドラジン水和物と反応させ、次いで沈殿した生成物を過剰のトリエチルオルトギ酸塩中に入れた混合物を還流することによって、短縮し得る。
本発明をここで、以下の非限定的な実施例によって例示する。この中で、特に指示のない限り：
(i) 収率は読者を助けとすることのみを意図したものであり、必ずしも勤勉なプロセス開発によって得られ得る最大値ではない；
(ii) 1H NMRスペクトルは、CDCl3中、テトラメチルシラン(TMS)を内部標準として用いて270MHzで測定され、そしてTMSに対する化学シフト(デルタ値)としてppmで表され、主ピークの指定のための従来的な略号を用いた：s、一重線；m、多重線；t、三重線；br、広幅；d、二重線。
実施例1
工程1
塩化チオニル(42ml)を60分間かけて、0℃に冷却した水(250ml)に滴下し、混合物の温度を0〜7℃の間に維持した。溶液を17時間かけて18℃まで温めた。塩化銅(I)(0.151g)を混合物に加え、そして得られた黄緑色溶液を氷／アセトン浴を用いて−3℃まで冷却した。
工程2
36％w/wの塩酸(135ml)を3-アミノ-2-クロロピリジン(17.3g)に攪拌しながら加え、混合物の温度を氷で冷却して30℃より低く維持した。反応混合物を氷／アセトン浴を用いて−5℃に冷却し、そして亜硝酸ナトリウム(10.0g)の水(40ml)溶液を45分間かけて滴下し、反応混合物の温度を−5℃と0℃との間に維持した。得られたスラリーを−2℃に冷却し、そして10分間攪拌した。
工程3
工程2のスラリーを−5℃に冷却し、そして工程1で得られた溶液に95分間かけて加え、反応温度を−3〜0℃の間に維持した(工程2からのスラリーは添加の間中−5℃に維持した)。添加が進むにつれ、固体が沈殿しはじめた。添加が完了したら、反応混合物を0℃で75分間攪拌した。懸濁した固体を減圧濾過によって採取し、水(2×125ml)で洗浄し、そして減圧下、35℃より低温で乾燥して2-クロロピリジン-3-スルホニルクロリド(19.6g；収率70%)を得た；融点42℃；NMR：7.50-7.60(m, 1H)、8.45-8.50(m, 1H)、8.72-8.75(m, 1H)。
あるいは、冷反応混合物をトルエン(100ml)で抽出し、水(2×100ml)で洗浄し、そしてトルエン抽出物を減圧(300mmHg)で共沸蒸留して乾燥して、生成物を単離した。次いで乾燥した生成物のトルエン溶液を次の反応に直接使用した。
実施例2〜10
実施例1で記載の手順と同様の手順を用いて、以下のスルホニルクロリドを適切なアミノピリジンまたはアミノベンゼンの比例的な量から得た：
Pyridinesulfonyl chloride and benzenesulfonyl chloride are useful in the manufacture of compounds having a variety of uses, such as the manufacture of pharmaceuticals or herbicides. For example, 2-chloropyridine-3-sulfonyl chloride is particularly useful in the production of endothelin antagonists as described in International Patent Application Publication No. WO 96/40681.
Many methods are known for the preparation of pyridinesulfonyl chloride (eg 2-chloropyridine-3-sulfonyl chloride) and benzenesulfonyl chloride. One such method, the diazonium salt of the corresponding aminopyridine (such as 3-amino-2-chloropyridine) or aromatic amine with sulfur dioxide using the presence of acetic acid, the CuCl or CuCl 2 as catalyst It involves reacting and then isolating the product by solvent extraction. Such methods are disclosed in WO 96/40681 and European Patent Application Publication Nos. 733629 and 618209. Similar methods are disclosed in Synthesis , (1969), Vol. 6, No. 1, pages 3-10 and Rec . Trav . Chim ., (1965), 84, 24-29.
A disadvantage of carrying out this process on a large scale is the difficulty associated with isolating the product free of impurities at the end of the reaction. In particular, it is often difficult to obtain a product that does not contain acetic acid, or to prevent the product from hydrolyzing to the corresponding sulfonic acid during work-up, on a large scale. A further disadvantage when performing this process on a large scale is the use of sulfur dioxide, a gaseous reagent. These disadvantages make this process unattractive for commercial scale operation.
Surprisingly, there is now a process for the production of pyridinesulfonyl chloride and certain benzenesulfonyl chlorides that avoids the use of both acetic acid and sulfur dioxide gas and overcomes the isolation problems faced by known processes. It's been found.
According to the present invention there is provided a process for the preparation of pyridinesulfonyl chloride or benzenesulfonyl chloride, wherein the benzene ring has one or more electron withdrawing groups, which process comprises aminopyridine or aminobenzene ( This includes the reaction of a diazonium salt (having one or more electron-withdrawing groups) and a mixture of thionyl chloride in water in the presence of an electron transfer catalyst.
A particular aspect of the present invention is a process for the preparation of pyridinesulfonyl chloride, which involves the reaction of a mixture of a diazonium salt of aminopyridine and thionyl chloride in water in the presence of an electron transfer catalyst.
A further particular aspect of the present invention is a process for the production of benzenesulfonyl chloride, wherein the benzene ring carries one or more electron withdrawing groups (more particularly one or two electron withdrawing groups). This process involves the reaction of a diazonium salt of aminobenzene (where the benzene ring has one or more electron withdrawing groups) and a mixture of thionyl chloride in water in the presence of an electron transfer catalyst. .
When referring to pyridinesulfonyl chloride or aminopyridine, it is understood that the pyridine ring may be unsubstituted or may have one or more substituents. Specific examples of the substituent include an electron withdrawing substituent.
Preferred electron transfer catalysts include, for example, cupric chloride (CuCl 2 ) and cuprous chloride (CuCl), and the latter is particularly the latter. Preferably 0.012 to 0.05 equivalent of catalyst (per equivalent of amino compound) is used.
Functional groups or substituents can be classified as electron withdrawing (-I) or electron donating (+ I) groups relative to hydrogen, according to J. March, Advanced Organic Chemistry, 4th edition, Wiley. & Well known as disclosed in & Sons. Typical electron withdrawing groups are referenced or listed in the above publications, which are incorporated herein by reference. Specific electron withdrawing groups include, for example, chloro, bromo, cyano, nitro, and carboxy.
The preparation of primary aromatic amines or heteroaromatic amine diazonium salts is well known in the field of organic chemistry and is by reaction of amines with nitrous acid. For the process of the present invention, nitrous acid is generated in situ by the conventional method of reaction of alkali metal nitrite (especially sodium nitrite) and mineral acid (especially hydrochloric acid) in the presence of an amino compound. Is convenient. The diazotization reaction is generally carried out at a temperature in the range of about +5 to -10 ° C, and preferably +1 to -4 ° C. It is preferred to use about 1-1.2 equivalents of alkali metal nitrite and 3-20 (more preferably 11-13) equivalents of concentrated (about 36%) hydrochloric acid (per amino compound equivalent). If the starting material is an aminobenzene having one or more electron withdrawing groups, the amine is added to the mineral acid and the mixture is added at 30-50 ° C. at 10-50 ° C. (to ensure complete salt formation). It is preferred to heat for 60 minutes, then cool and add aqueous sodium nitrite. The water added to dissolve the sodium nitrite is usually between 1 and 5 volumes, based on the input weight of the amino compound, but instead, solid nitrite is added in small portions to the mixture of amines in hydrochloric acid. May be added. Since the diazonium salt is unstable, the diazonium salt solution or slurry thus produced is immediately after preparation while maintaining the temperature of the solution or slurry between about +1 to -4 ° C throughout the addition. It is preferable to use for.
It is preferred to use 2-12 equivalents of thionyl chloride per equivalent of amino compound, and in particular 4-5 equivalents of thionyl chloride.
The water added for thionyl chloride dissolution is preferably between 5 and 30 volumes (and more preferably between 10 and 20 volumes) of water, based on the input weight of the amino compound.
Maintain the mixture of thionyl chloride and water at 18-25 ° C (conveniently near ambient temperature) for 1-48 hours (conveniently 15-20 hours (eg overnight)) prior to reaction with the diazonium salt. Is preferred.
The diazonium salt solution should be added as quickly as possible, maintaining a consistent exothermic reaction at temperatures between -10 ° C and + 5 ° C, and preferably between -4 ° C and + 1 ° C. preferable. After the addition, the reaction is preferably maintained near this temperature for 15-90 minutes.
The product can be isolated by extraction into a suitable solvent, such as a hydrocarbon, chlorinated hydrocarbon, or water-immiscible ether solvent (eg, dichloromethane, diethyl ether or preferably toluene). The absence of acetic acid in the reaction mixture means that difficulties associated with the presence of acetic acid in the solvent extract (and subsequent removal thereof) are avoided. The advantage of using toluene as the extraction solvent is that the extract can be washed with water, and any residual traces of water and entrained HCl can be removed by azeotropic distillation, and the product is obtained as a toluene solution. This toluene solution can then be used directly in subsequent reactions or the toluene can be removed under reduced pressure to give the product, such as n-hexane, isohexane or cyclohexane. And can be recrystallized in high purity from non-polar solvents.
Alternatively, if the product is a solid sulfonyl chloride, it can precipitate from the reaction mixture and be collected by filtration instead of solvent extraction.
The process of the invention is particularly suitable for the preparation of 2-halogenopyridine-3-sulfonyl chlorides, such as 2-chloropyridine-3-sulfonyl chloride.
A further surprising advantage found when using the process of the present invention for the preparation of 2-chloro-3-pyridinesulfonyl chloride is that the product precipitates in high purity from the reaction mixture as the free base and is collected by filtration. It can be done. All previously known methods for preparing 2-chloro-3-pyridinesulfonyl chloride from the diazonium salt of 3-amino-2-chloropyridine require acetic acid isolation and require isolation by extraction. I think that.
The present invention also provides a process for the preparation of certain endothelin antagonists disclosed in WO 96/40681, which is incorporated herein by reference.
Thus, according to another aspect, the present invention provides a compound of formula I
(a) providing 2-chloropyridine-3-sulfonyl chloride by reaction of a diazonium salt of 3-amino-2-chloropyridine with a mixture of thionyl chloride in water in the presence of a charge transfer catalyst;
(b) Reaction of 2chloropyridine-3-sulfonyl chloride with isobutyl N- (3-methoxy-5-methylpyrazin-2-yl) carbamate in the presence of an alkali metal hydride in an inert solvent Providing chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide;
(c) 2-chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide and a boronic acid of formula II
Thereafter, where a pharmaceutically acceptable salt of a compound of formula I is required, this is obtained by reaction with a suitable acid or base to give a physiologically acceptable ion, or any other conventional Obtained by the salt formation procedure.
Step (a) may be performed as described above.
Step (b) can be performed, for example, using an alkali metal hydride (eg, sodium or potassium hydride) in an inert solvent such as DMF, pyridine or toluene. This reaction is carried out at a temperature in the range of, for example, 0 ° C to 70 ° C. A typical example of step (b) is described in Example 1 (ii) of WO 96/40681. For example, the compound isobutyl N- (3-methoxy-5-methylpyrazin-2-yl) carbamate can be obtained as described in Example 1 of WO 96/40681.
In step (c), suitable catalysts include, for example, tetrakis (triphenylphosphine) nickel (0), bis (triphenylphosphine) nickel (II) chloride, nickel (II) chloride, bis (triphenylphosphine) palladium. (II) chloride, palladium (II) chloride, and tetrakis (triphenylphosphine) palladium (0), the last of which is the preferred catalyst. Suitable bases for use in the reaction are, for example, alkali metal alkoxides (e.g. sodium methoxide or sodium ethoxide), alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide), alkali metal carbonates ( For example, sodium carbonate or potassium carbonate), or an organic base (eg, tri (1-6C) alkylamine, eg, triethylamine). Of these, sodium carbonate is the preferred base. Coupling usually involves a suitable solvent or diluent such as hydrocarbon (e.g. toluene or xylene), ether (e.g. dioxane or tetrahydrofuran), (1-4C) alcohol (e.g. methanol, ethanol or butanol), water or It is carried out in the presence of a mixture thereof (for example a mixture of toluene, ethanol and water, which is preferred). The reaction is usually carried out at a temperature in the range of, for example, 50 to 150 ° C., and is conveniently carried out at or near the reflux temperature of the solvent or solvent mixture used. An example of step (c) is described in Example 1 (iii), 11 (ii), 12 (ii), 13 (ii), 14 (ii), 58 (vii) and 64 (iv) of WO 96/40681 Is done. Alternatively, the coupling can be performed under aqueous conditions using a fluoride ion source, for example, as in Example 96 (ii) of WO 96/40681, under reflux in a mixture of toluene and water. Performed with potassium.
Removal of the isobutoxycarbonyl protecting group can be performed after isolation of the protected product under basic conditions, e.g. using sodium hydroxide or alkoxide (e.g. methoxide) in a suitable solvent such as methanol. (Eg as described in Examples 1, 11, 12, 13, 14, 58 and 64 of WO 96/40681). Alternatively, the isobutoxycarbonyl group can be removed by in situ hydrolysis, for example, by adding additional water to the reaction mixture.
This process is particularly suitable for the preparation of compounds of formula I where R is 2-carboxy-2-methylpropyl.
According to another aspect, the present invention provides a process for the preparation of compounds of formula I wherein R is 1,3,4-oxadiazol-2-yl. This process includes the above steps (a) and (b), then the following additional steps:
(i) 2-chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide and 4-methoxycarbonylphenylboronic acid (or its anhydride or ester) ) In the presence of a fluoride ion source and in aqueous conditions, N- (isobutoxycarbonyl) -2- (4-methoxycarbonylphenyl) -N- (3-methoxy-5-methylpyrazine-2- Yl) providing pyridine-3-sulfonamide;
(ii) a step of removing the isobutoxycarbonyl protecting group;
(iii) converting the methyl ester (—CO.OCH 3 ) group to the corresponding hydrazide (—CONHNH 2 ); and
(iv) converting the hydrazide group to a 1,3,4-oxadiazol-2-yl moiety, after which a pharmaceutically acceptable salt of a compound of formula I is required, This can be obtained by reaction with a suitable acid or base to give a physiologically acceptable ion, or by any other conventional salt formation procedure.
Step (i) can be performed, for example, using potassium fluoride as the fluoride ion source and using xylene, methanol and water, or a mixture of toluene and water as the solvent. The reaction is conveniently carried out at the reflux temperature of the solvent mixture used. A typical example of step (i) is illustrated in Example 30 (ii) of WO 96/40681.
Step (ii) can be performed, for example, under basic conditions, for example, using a mixture of methanol and aqueous ammonia, or sodium methoxide in methanol. This can be done after first isolating the product obtained in (i) (as shown in Example 32 of WO 96/40681), or by diluting the reaction mixture of (i) with water, The organic phase is then separated, filtered, and the filtrate is diluted with methanol and then aqueous ammonia may be added. The product can then be isolated by adding water and precipitated by adding acetic acid.
Step (iii) can be performed, for example, by reacting the product of step (ii) with hydrazine hydrate in a suitable solvent (eg, dichloromethane and water). The hydrazide precipitates as the hydrazine salt and can be converted to the free hydrazide by adding aqueous hydrochloric acid and isolated by filtration.
Step (iv) can be performed, for example, by refluxing a mixture of the product of step (iii) in excess triethylorthoformate for 24 hours. The product precipitates on cooling. Alternatively, steps (ii), (iii) and (iv) may be carried out as shown in Example 36 of WO 96/40681, with the product of step (i) being refluxed, such as methanol, ethanol, acetonitrile or tetrahydrofuran. It can be shortened by reacting with hydrazine hydrate in a simple solvent and then refluxing the mixture of precipitated product in excess triethylorthoformate.
The invention will now be illustrated by the following non-limiting examples. Unless otherwise indicated:
(i) Yields are intended only to assist readers and are not necessarily the maximum values that can be obtained through diligent process development;
(ii) 1 H NMR spectrum was measured at 270 MHz in CDCl 3 using tetramethylsilane (TMS) as an internal standard and expressed in ppm as the chemical shift (delta value) relative to TMS, with the designation of the main peak. Conventional abbreviations for: s, single line; m, multiple line; t, triple line; br, wide line; d, double line.
Example 1
Process 1
Thionyl chloride (42 ml) was added dropwise over 60 minutes to water (250 ml) cooled to 0 ° C., and the temperature of the mixture was maintained between 0-7 ° C. The solution was warmed to 18 ° C. over 17 hours. Copper (I) chloride (0.151 g) was added to the mixture and the resulting yellow-green solution was cooled to −3 ° C. using an ice / acetone bath.
Process 2
36% w / w hydrochloric acid (135 ml) was added to 3-amino-2-chloropyridine (17.3 g) with stirring and the temperature of the mixture was cooled below ice and kept below 30 ° C. The reaction mixture was cooled to −5 ° C. using an ice / acetone bath, and a solution of sodium nitrite (10.0 g) in water (40 ml) was added dropwise over 45 minutes, and the temperature of the reaction mixture was adjusted to −5 ° C. and 0 ° C. And maintained between. The resulting slurry was cooled to −2 ° C. and stirred for 10 minutes.
Process 3
Cool the step 2 slurry to −5 ° C. and add to the solution obtained in step 1 over 95 minutes to maintain the reaction temperature between −3 to 0 ° C. (the slurry from step 2 was added during the addition). Maintained at -5 ° C). As the addition proceeded, solid began to precipitate. When the addition was complete, the reaction mixture was stirred at 0 ° C. for 75 minutes. The suspended solid was collected by vacuum filtration, washed with water (2 × 125 ml) and dried under reduced pressure below 35 ° C. to give 2-chloropyridine-3-sulfonyl chloride (19.6 g; 70% yield) Melting point 42 ° C; NMR: 7.50-7.60 (m, 1H), 8.45-8.50 (m, 1H), 8.72-8.75 (m, 1H).
Alternatively, the cold reaction mixture was extracted with toluene (100 ml), washed with water (2 × 100 ml), and the toluene extract was azeotropically distilled under reduced pressure (300 mmHg) to isolate the product. The dried product in toluene was then used directly in the next reaction.
Examples 2-10
Using a procedure similar to that described in Example 1, the following sulfonyl chlorides were obtained from proportional amounts of the appropriate aminopyridine or aminobenzene:
Claims (9)
(a) 3-アミノ-2-クロロピリジンのジアゾニウム塩と水中の塩化チオニルの混合物との電荷移動触媒存在下での反応により、2-クロロピリジン-3-スルホニルクロリドを与える工程；
(b) 2-クロロピリジン-3-スルホニルクロリドとイソブチルN-(3-メトキシ-5-メチルピラジン-2-イル)カルバメートとの水素化アルカリ金属存在下での不活性溶媒中での反応により、2-クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドを与える工程；
(c) 2-クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドと式IIのボロン酸
その後、式Ｉの化合物の薬学的に受容可能な塩が必要とされる場合、これが生理学的に受容可能なイオンを与える適切な酸または塩基との反応によって得られ、あるいは任意の他の従来の塩形成手順によって得られる、プロセス。Compound of formula I
(a) providing 2-chloropyridine-3-sulfonyl chloride by reaction of a diazonium salt of 3-amino-2-chloropyridine with a mixture of thionyl chloride in water in the presence of a charge transfer catalyst;
(b) reaction of 2-chloropyridine-3-sulfonyl chloride with isobutyl N- (3-methoxy-5-methylpyrazin-2-yl) carbamate in the presence of an alkali metal hydride in an inert solvent, Providing 2-chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide;
(c) 2-chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide and a boronic acid of formula II
Thereafter, where a pharmaceutically acceptable salt of a compound of formula I is required, this is obtained by reaction with a suitable acid or base to give a physiologically acceptable ion, or any other conventional Process obtained by a salt formation procedure.
(a) 3-アミノ-2-クロロピリジンのジアゾニウム塩と水中の塩化チオニルの混合物との電荷移動触媒存在下での反応により、2-クロロピリジン-3-スルホニルクロリドを与える工程；
(b) 2-クロロピリジン-3-スルホニルクロリドとイソブチルN-(3-メトキシ-5-メチルピラジン-2-イル)カルバメートとの水素化アルカリ金属存在下での不活性溶媒中の反応により、2-クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドを与える工程；
(c) 2-クロロ-N-イソブトキシカルボニル-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-スルホンアミドと4-メトキシカルボニルフェニルボロン酸(あるいはその無水物またはエステル)との、フッ化物イオン源存在下および水性条件下での反応により、N-(イソブトキシカルボニル)-2-(4-メトキシカルボニルフェニル)-N-(3-メトキシ-5-メチルピラジン-2-イル)ピリジン-3-スルホンアミドを与える工程；
(d)イソブトキシカルボニル保護基の除去工程；
(e)メチルエステル(-CO.OCH3)基を対応のヒドラジド(-CONHNH2)に転化する工程；および
(f)ヒドラジド基を1,3,4-オキサジアゾール-2-イル部分に転化する工程；を包含し、
その後、式Ｉの化合物の薬学的に受容可能な塩が必要とされる場合、これが生理学的に受容可能なイオンを与える適切な酸または塩基との反応によって得られ、あるいは任意の他の従来の塩形成手順によって得られる、プロセス。Compounds of formula I:
(a) providing 2-chloropyridine-3-sulfonyl chloride by reaction of a diazonium salt of 3-amino-2-chloropyridine with a mixture of thionyl chloride in water in the presence of a charge transfer catalyst;
(b) Reaction of 2-chloropyridine-3-sulfonyl chloride with isobutyl N- (3-methoxy-5-methylpyrazin-2-yl) carbamate in the presence of an alkali metal hydride in an inert solvent Providing -chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide;
(c) 2-chloro-N-isobutoxycarbonyl-N- (3-methoxy-5-methylpyrazin-2-yl) pyridine-sulfonamide and 4-methoxycarbonylphenylboronic acid (or its anhydride or ester) Of N- (isobutoxycarbonyl) -2- (4-methoxycarbonylphenyl) -N- (3-methoxy-5-methylpyrazin-2-yl) by reaction in the presence of a fluoride ion source and in aqueous conditions ) Providing pyridine-3-sulfonamide;
(d) a step of removing the isobutoxycarbonyl protecting group;
(e) converting the methyl ester (—CO.OCH 3 ) group to the corresponding hydrazide (—CONHNH 2 ); and
(f) converting the hydrazide group to a 1,3,4-oxadiazol-2-yl moiety;
Thereafter, where a pharmaceutically acceptable salt of a compound of formula I is required, this is obtained by reaction with a suitable acid or base to give a physiologically acceptable ion, or any other conventional Process obtained by a salt formation procedure.
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| GB9704762.5 | 1997-03-07 | ||
| GBGB9704762.5A GB9704762D0 (en) | 1997-03-07 | 1997-03-07 | Chemical process |
| PCT/GB1998/000651 WO1998040332A1 (en) | 1997-03-07 | 1998-03-03 | Process for the manufacture of arylsulfonyl chloride |
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| JP2001514648A JP2001514648A (en) | 2001-09-11 |
| JP4046360B2 true JP4046360B2 (en) | 2008-02-13 |
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| EP (1) | EP0973704B1 (en) |
| JP (1) | JP4046360B2 (en) |
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| PT (1) | PT973704E (en) |
| WO (1) | WO1998040332A1 (en) |
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| GB0219660D0 (en) | 2002-08-23 | 2002-10-02 | Astrazeneca Ab | Therapeutic use |
| GB0403744D0 (en) * | 2004-02-20 | 2004-03-24 | Astrazeneca Ab | Chemical process |
| US7625895B2 (en) * | 2007-04-12 | 2009-12-01 | Hoffmann-Le Roche Inc. | Diphenyl-dihydro-imidazopyridinones |
| EA019774B1 (en) | 2008-12-29 | 2014-06-30 | Санофи | Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof |
| US20120309796A1 (en) | 2011-06-06 | 2012-12-06 | Fariborz Firooznia | Benzocycloheptene acetic acids |
| CN102491973A (en) * | 2011-12-15 | 2012-06-13 | 南京友杰医药科技有限公司 | Synthetic method for ZD (Zero Defects)-4054 |
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| DE859461C (en) * | 1942-12-02 | 1952-12-15 | Bayer Ag | Process for the preparation of aromatic sulfonic acid halides |
| CH590830A5 (en) * | 1973-02-20 | 1977-08-31 | Hoechst Ag | |
| US4714700A (en) * | 1982-04-20 | 1987-12-22 | Choay S.A. | N-substituted 2,4-dialkoxy benzenesulfonamides and pharmaceutical compositions |
| UA58494C2 (en) * | 1995-06-07 | 2003-08-15 | Зенека Лімітед | N-heteroaryl-pyridinesulfonamide derivatives, pharmaceutical composition, process for preparing thereof and method for endothelin influence counteraction |
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- 1998-03-03 EP EP98908219A patent/EP0973704B1/en not_active Expired - Lifetime
- 1998-03-03 DK DK98908219T patent/DK0973704T3/en active
- 1998-03-03 JP JP53933698A patent/JP4046360B2/en not_active Expired - Fee Related
- 1998-03-03 WO PCT/GB1998/000651 patent/WO1998040332A1/en active IP Right Grant
- 1998-03-03 DE DE69826845T patent/DE69826845T2/en not_active Expired - Lifetime
- 1998-03-03 PT PT98908219T patent/PT973704E/en unknown
- 1998-03-03 US US09/380,478 patent/US6531605B1/en not_active Expired - Fee Related
- 1998-03-06 ZA ZA981933A patent/ZA981933B/en unknown
-
2003
- 2003-01-22 US US10/348,229 patent/US6943254B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998040332A1 (en) | 1998-09-17 |
| GB9704762D0 (en) | 1997-04-23 |
| ATE278651T1 (en) | 2004-10-15 |
| AU6630098A (en) | 1998-09-29 |
| EP0973704B1 (en) | 2004-10-06 |
| DK0973704T3 (en) | 2005-01-17 |
| EP0973704A1 (en) | 2000-01-26 |
| US20030162973A1 (en) | 2003-08-28 |
| PT973704E (en) | 2005-01-31 |
| DE69826845T2 (en) | 2006-03-09 |
| DE69826845D1 (en) | 2004-11-11 |
| ES2227807T3 (en) | 2005-04-01 |
| ZA981933B (en) | 1998-09-07 |
| US6531605B1 (en) | 2003-03-11 |
| US6943254B2 (en) | 2005-09-13 |
| JP2001514648A (en) | 2001-09-11 |
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